The 100 top-cited articles in menopausal syndrome: a bibliometric analysis

Background Significant scientific research has been conducted concerning menopausal syndrome(MPS), yet few bibliometric analyses have been performed. Our aim was to recognise the 100 most highly cited published articles on MPS and to analytically evaluate their key features. Methods To identify the 100 most frequently cited articles, a search was conducted on Web of Science using the term 'menopausal syndrome'. Articles that matched the predetermined criteria were scrutinised to obtain the following data: citation ranking, year of publication, publishing journal, journal impact factor, country of origin, academic institution, authors, study type, and keywords. Results The publication period is from January 1, 2000, to August 31, 2022. The maximum number of citations was 406 and in 2012. The median citations per year was 39.70. Most of the articles focused on treatment and complications. These articles were published in 36 different journals, with the Journal of MENOPAUSE having published the greatest number (14%). Forty-eight articles (48%) were from the United States, with the University of Pittsburgh being the leading institute (9%). Joann E. Manson was the most frequent first author (n = 6). Observational studies were the most frequently conducted research type (n = 53), followed by experimental studies (n = 33). Keyword analysis identified classic research topics, including genitourinary syndrome of menopause, bone mineral density (BMD), and anti-mullerian hormone (AMH) loci. Conclusion Using bibliometrics, we conducted an analysis to identify the inadequacies, traditional focal points, and potential prospects in the study of MPS across current scientific areas. Treatment and complications are at the core of MPS research, whereas prediction and biomarkers have less literature of high quality. There is a necessity for innovative analytical metrics to measure the real effect of these papers with a high level of citation on clinical application.


Introduction
Menopausal syndrome (MPS) is a series of disorders of autonomic nervous system, accompanied by neuropsychological symptoms, caused by estrogen fluctuation or decrease in the period of before and after menopause.The core reason lies in the gradual decline of ovarian function, including natural menopause and artificial menopause.In particular, this is not the end of old age, but the beginning of senescence in biological age.The life expectancy of women further increased to 80.88 years [1], which means the irreversible state of low estrogen

Results
The 100 top-cited articles were summarized in descending order according to the number of total citations (Table 1).With the publishing date from 2012 to 2022, the largest number of literature published in the year 2012, 2013, 2014, respectively.Among 100 top-cited articles, 53 publications were observational study.Next up were experimental study(n = 33), in vivo study(n = 10), in vitro study(n = 3).Of 36 different journals, MENO-PAUSE (n = 14), J CLIN ENDOCR METAB (n = 12), MATURITAS(n = 6) and JAMA related journal (n = 6) published the greatest number of these articles.The median times cited all databases of MPS was 111 (IQR, 98. 25-147.5).The maximum of total citations was 406 in BRIT MED J, which reported by Hvidovre Univ Hosp of Denmark in 2012.And, the median of average times per year of cited all databases of MPS was 14.07 (IQR, 10.44-20.07).And, the maximum of average times per year was 62.5 in CELL, which reported by the scientific researchers of Chinese Academy of Sciences of China in 2020.

Active authors
In order to finding the information on influential author and research groups, the fruitful partnership network of authors was constructed (Fig. 1).Of the top 2 active authors (published above 3 articles), Manson, joann e. contributed the most papers (6 publications, 5%), focusing on MPS related biological aging, breast cancer, cardiovascular risk factors, vasomotor symptoms, cognitive function, vaginal estrogens.Followed by Freeman, ellen w., Hodis, howard n., Budoff, matthew j. with 5, 4 and 4 publications respectively, which also paid more attention on the anxiety or depression on the above MPS related topic.We conducted correlation analyses to assess the relationships between journal impact factors and both citation frequency and average citations per article.Initial normality tests for these variables revealed that they did not follow a normal distribution (P < 0.000), thus Spearman's rank correlation was utilized.A weak positive correlation was identified between journal impact factors and average citation counts (r = 0.258, P = 0.010), and a low-to-moderate positive correlation between journal impact factors and citation frequency (r = 0.310, P = 0.002).

Active countries and institutions
The partnership network of countries and institutions was constructed.In the database, with established good cooperative relations with scientists from many countries, the leading country was the USA, which published 48 articles, followed by Italy (n = 19), England (n = 15), and Australia (n = 12) (Fig. 2).As the most productive institution,University of Pittsburgh has been published Table 1 The top 100 cited articles in menopausal syndrome Observational study [13] Vulvovaginal atrophy (VVA) Observational study [111] Table 1 (continued) Observational study [112] The protection of primordial follicle oocyte Observational study [134] Vulvovaginal  9 articles (Fig. 3).Followed by Università degli Studi di Pavia (n = 8), Harvard University (n = 7) and Stanford University(n = 7).

Active Keywords
CiteSpace 5.8.R3 was used to construct the keywords analysis, which showed a reasonable description of research focus in MPS.Of the 10 types in keywords, the top 5 types were interlace, genitourinary syndrome of menopause, bone mineral density (BMD), anti-mullerian hormone (AMH), loci (Fig. 4).Of the 10 types in classification, the top 5 types were obstetrics and gynecology, cardiac and cardiovascular systems, physiology, reproductive biology, genetics and heredity (Fig. 5).Of the 10 types in title, the top 5 types were individual patient data, cardiovascular event, body composition, ovarian reserve, estrogen treatment (Fig. 6).These involve the prominent problems from the vasomotor symptom (VMS) in MPS to vulvovaginal atrophy and genitourinary syndrome of menopause in menopausal related diseases(Table 2).

Discussion
MPS has developed into a global health epidemic.Under the circumstances that the aging society has formed and gradually intensified, it will suffer more chronic diseases especially in countries and regions with high life In this bibliometric study and systematic review of MPS related top-cited articles, the analysis showed the information of authorship, country, institution and keywords.It systematically summarized the development status in this field in the past 10 years in order to provide ideas for future research.

Genitourinary syndrome of menopause
The condition of hypoestrogenism related to menopause has a strong negative impact on vaginal and urinary health, often leading to a condition called genitourinary syndrome (GSM), a term put forward in 2014 [7], although it was used to be called vulvar and vaginal atrophy (VVA).Approximately 50% of postmenopausal women have vulvar, vaginal, and clitoral symptoms, including vaginal dryness, irritation, and itching; sexually related problems such as dyspareunia; and urinary problems including dysuria and recurrent urinary tract infections [8,9].The most recent surveys indicated that VVA affected most peri-and postmenopausal women with a prevalence ranging from 36% to almost 90% [10], so GSM is a common, under-diagnosed, and under-treated disorder [11,12].Measures to improve its early detection and its appropriate management are needed.However, significant barriers to treatment include a lack of knowledge about VVA, reluctance to discuss symptoms with healthcare professionals (HCPs), safety concerns, inconvenience, and inadequate symptom relief from available treatments [13].
People pay more attention to non-hormonal therapy and newer treatment options including selective estrogen receptor modulators, vaginal dehydroepiandrosterone, and laser therapy, etc. Treatment with the fractional CO2 laser has been proven to be feasible and induced a significant improvement of VVA symptoms by ameliorating vaginal health in postmenopausal women as well as a significant improvement of sexual function and satisfaction with sexual life [14,15].Its security has also been assessed, which indicated that it could produce a remodeling of vaginal connective tissue without causing damage to surrounding tissue [16].Vaginal erbium laser is the second-generation thermotherapy for the genitourinary syndrome of menopause, and recent data suggested that laser energy can be used for the treatment of postmenopausal women suffering from GSM with rapid and more long-lasting effects compared to topical estriol treatment [17,18].

Menopausal hormone therapy
The most-cited article was published by Schierbeck, Louise Lind from Denmark published in BRITISH MEDI-CAL JOURNAL in 2012 (cited 397 times) [19].It focus Table 2 Top 14 keywords with the strongest citation bursts on hormone replacement therapy (MHT).Although the situation has changed a lot since the 1942 approval of conjugated equine estrogens, menopausal hormone therapy (MHT) remains the most standard scheme to collectively address the menopausal related symptoms (such as vasomotor symptoms) and additional concerns (such as postmenopausal osteoporosis) [20].However, including oestrogen or an oestrogenic compound, MHT is also associated with risks of serious health conditions including breast, ovarian and endometrial cancer, stroke and venous thromboembolism, etc.. Additionally, MHT related health risks are proportional to the duration of use.It should be used in before the average menopause age, not all age groups [21,22]; and racial differences should be taken into account [23,24].Although the development of transdermal or vaginal drug delivery has greatly reduced the side effects, the acceptance of menopausal suffers is still low [25,26].Therefore, the optimal duration of MHT cannot be recommended, but the initial indications of MHT and the balance of interests and risks for each woman must be strictly considered (Mendoza et al.In recent years, studies have conducted in-depth research on the mechanism of adverse events (AEs) caused by MHT.Dydrogesterone has displayed a favorable safety and tolerability profile during its 60-year use.AEs concerning breast cancer risk, endometrial cancer risk, venous thromboembolism risk, and cardiovascular risk were found to be minimal when dydrogesterone was used as part of a menopausal hormone therapy regimen lasting ≤ 260 weeks [27].Over a (median) 18-year follow-up period (1993-2016), conjugated equine estrogens nominally significant reduce for coronary heart disease, breast cancer, hip fracture, and all-cause mortality.However, estrogens plus progestin increased breast cancer risk, and reduced endometrial cancer risk [28].With fewer AEs and more benefits in better sexual life, skin condition and physical activity, alternative therapies receives more and more attention [29].Compared with, medroxyprogesterone acetate (MPA) and norethisterone (NET) which increased breast cancer risk, evidence suggests a differential effect of MHT containing E2 or natural progesterone (P4) and those containing CEE or progestins, with some evidence trending to a potentially better safety profile with E2 and/or P4 [30][31][32]

Cardiovascular disease
The decrease in estrogen level causing the dysfunction of the autonomic nervous system and the decrease of the protective effect on blood vessels, which increases the vasodilation and contraction symptoms that may adversely affect vascular health as well as the occurrence of cardiovascular diseases [33], such as atherosclerosis, stroke, hypertension, and arrhythmias.In the cardiovascular system, aging is accompanied by increased stiffness, increased fibrosis, loss of contractile reserve, increased ROS and endothelial dysfunction.All of these factors contribute to cardiovascular dysfunction [34].Endothelial dysfunction, on the other hand, is characterized by reduced endothelium-dependent vasodilation, a biomarker of aging, and an important predictor of cardiovascular events in women [35].Menopausal hormone therapies (MHT) may modulate endothelial function and reduce development of vascular lesions.
Sex hormone levels, especially those in which total testosterone is higher compared to estrogen in the postmenopausal [36], that is, lower endogenous estrogen levels resulting from menopausal transition [37] and higher endogenous androgens [38], may mediate the increased risk of cardiovascular disease (including blood pressure, C-reactive protein (CRP), and insulin resistance) in postmenopausal women [39].The Danish Osteoporosis Prevention Study (DOPS) randomized trial found that women treated with estradiol or in combination with sequential norethindrone acetate in the early postmenopausal period had a significantly lower risk of coronary heart disease than untreated women, demonstrating the effectiveness of hormone replacement therapy for cardiac diseases such as heart failure or myocardial infarction in perimenopausal women [40].The Early versus Late Intervention Trial with Estradiol (ELITE) suggests that the effect of hormone therapy on cardiovascular disease varies may depend on the timing of initiation of treatment relative to the perimenopausal period.Carotid intima-media thickness (CIMT) has been found to be inversely correlated with plasma total estradiol levels in the late postmenopausal period [41].Early Menopausal hormone therapy (MHT) did not affect progression of atherosclerosis despite improving some markers of CVD risk [42].Oral estradiol therapy within 6 years of postmenopausal significantly reduced CIMT progression but not when it was initiated in women who were 10 or more after menopause [41].Therefore, grasping the duration of menopause is helpful for the prevention and treatment of cardiovascular disease risk in menopausal women.

Breast cancer
In 2020, female breast cancer ranked first in the global incidence of malignant tumors, with about 2.3 million new cases, accounting for 11.7% of all new cases [43].Numerous studies have shown that women have an increased risk of breast cancer after menopause.Changes in hormone levels are the underlying cause of the risk of disease and decreased serum luteinizing hormone and follicle-stimulating hormone levels after menopause are associated with increased ER and PR expression and decreased HER2 expression in breast cancer patients [44,45].Total testosterone TT, testosterone BT, dehydroepiandrosterone, and estradiol increase the risk of different subtypes of BCs [46].Obesity is one of the main risk factors causes especially an increased incidence of ER + , low-grade breast cancer [47,48].Obesity-induced inflammation plays a role in the development and progression of breast cancer, and plasma levels of measured inflammatory biomarkers are positively associated with breast cancer risk in postmenopausal women, but the association between measured inflammatory biomarkers and breast cancer risk did not vary by breast cancer subtype [49], and serum uric acid plays an important mediating role in the obesity-breast cancer relationship [50,51].MHT use was associated with a lower risk of breast cancer mortality following surgical menopause before 45 years, at 45-49 years or at ≥ 50 years, and the association between MHT use and the risk of breast cancer mortality did not differ by MHT use duration (< 6 or 6-20 years).MHT use was also associated with a lower risk of breast cancer mortality following natural menopause before 45 years or hysterectomy before 45 years [52].MHT use was associated with an increased risk of breast cancer (odds ratio [OR] 1.12, 95% CI 1.09-1.15).And, this risk appears predominantly mediated through formulations containing synthetic progestins.micronized progesterone may be the safer progestogen to be used [53][54][55].Nearly half of the effect of MHT on the risk of hormone receptorpositive BC is mediated by breast density.Indicate that we should use MHT with caution for women [56,57].cCNE2 may be a candidate gene for estrogen-progestininduced breast cancer.But strong evidence is still lacking to support for common genetic variants altering the effect of MHT on breast cancer risk in estrogen-progestin MHT combinations or in estrogen receptor (ER) positive cases [58,59].The gut microbiota can influence breast carcinogenesis, but it remains to be investigated whether there are differences in the abundance, diversity, and composition of the gut microbiota between postmenopausal breast cancer patients and controls [60,61].Lack of physical activity, high postmenopausal body mass index, alcohol consumption, and use of menopausal hormone therapy are known risk factors for breast cancer [62][63][64].There was a definite association between modifiable lifestyle factors and 10-year all-cause mortality.The strongest association was found between BMI ≥ 30 kg/m2 and all-cause mortality compared with BMI 18.5 ~ 25 kg/m2 [HR (95% confidence interval, 1.19,1.06~ 1.34)].There was no evidence of associations between modifiable risk factors and 10-year mortality differed by subtype [65,66].

Osteoporosis
Osteoporosis is recognized as the most common complication of menopause, which closely related to fracture and osteodynia [67].A new discovery showed that hearing and body balance at baseline exceeded initial BMD in predicting incident fractures in menopausal women with osteoporosis regardless of treatment during 25-year follow-up [68,69].Genome-wide association studies (GWAS) identified 12 loci that were significantly associated with BMD at any site in Chinese population, and rs1239055408 G > GA (KCNJ2) was associated with BMD only in women [70].And, High-fat diet-induced obesity augments the deleterious effects of estrogen deficiency on bone, which resulting in accelerated cellular senescence, expansion of BMAT and impaired bone formation leading to decreased bone mass [71].Longer leukocyte telomere length (LTL) was weakly associated with reduced risk of any incident fracture in women, however with less evidence in men [72].Additionally, with a higher bone loss rate in surgically induced menopausal women compared with a natural process, MHT could significantly suppress the high bone remodeling [73].In a Women's Health Initiative (WHI) hormone therapy trials including 25,389 postmenopausal women aged 50-79 years, MHT reduced the risk of fracture regardless of baseline FRAX fracture probability and falls history [74].The MHT scheme of percutaneous estradiol gel (1.5 mg/day) plus oral micronized progesterone (100 mg/day) for 4 years has a low probability in fracture recurrence and mortality [75].Erxian Decoction (EXD), as a commonly used alternative therapy of traditional Chinese medicine, is exerted therapeutic effects for OP through multiple functional signal pathways [76].Phytoestrogens represented by the nanoparticles of betulinic acid (BA/NPs), as an naturally occurring PPAR-γ inhibitor, has great potential to improve osteoporosis in the in vivo and in vitro model [77][78][79].

Cognitive impairment
E2 is important for regulating hippocampal learning and memory.With the increase of subjective cognitive dysfunction and elevated rates of depression in this period, premature estrogen decline can lead to mild cognitive impairment (MCI), even Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and vascular dementia (VaD) [80,81].However, as continued interest and debate, whether the MHT cure or prevent cognitive impairment or not.Recent research shows that MHT to improve cognitive functioning has only a few scenarios where it would be recommended and that particular caution may be warranted for carriers of the APOE ε4 allele [82].Additionally, women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from MHT treatment [83].A meta-analysis including 10 RCTs with 2,818 participants showed that current available evidence does not support MHT had no effect on verbal memory in postmenopausal women, and also may impair some domains of short-term memory [84].Further research findings that it has shown a slightly increased risk of developing AD among long term users of oestrogen-progestogen therapies, rather than taking oestrogen-only therapy [85].A new perspective study of Functional cerebral asymmetry (FCA) discovered that right hemisphere is mainly affected by aging, and hormonal modulation improves the interplay between the two hemispheres and reduces FCA [86].And also, a PET Study showed post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions, but were not moderated by Aβ burden or APOEε4 [87].Additionally, following lower side effects compared with MHT, phytoestrogens as neuroprotective agents or epigenetic modifiers recover and maintain cognitive functions [88,89].But, very little is known regarding the regulation of synaptic plasticity genes, and also the precise regulation mechanism needs to be further explored.Moreover, postmenopausal status and a family history of dementia were more frequent among women who had had COVID-19 [90].

Glucolipid metabolism disorder
Changes in hormone levels lead to abnormalities in lipid metabolism with elevated serum total cholesterol, LDL cholesterol, apolipoproteins, and triglycerides, and decreased high-density lipoprotein cholesterol (HDL-C) [91].Reduced energy expenditure due to reduced lipid oxidation and reduced leptin sensitivity in menopausal women [92].Postmenopausal women have a lower gut microbiome diversity, slightly similar to that of men, and are involved in sex hormone retention.One study found that the gut microbe Bacteroides fragilis contributes to obesity in perimenopausal women by suppressing acetic acid levels [93,94].In addition, overweight or obese women have more severe and moderate menopausal symptoms [95].Central adipose tissue accumulation, production of cytokines, and other factors contribute to an increased risk of developing T2DM by causing lowgrade systemic inflammation and insulin resistance [96].The earlier the age of menopause, the higher the risk of developing type 2 diabetes mellitus in women.Autoimmune destruction of follicles, insulin deficiency, and exogenous hyperinsulinemia in diabetic patients disrupt the normal function of the female reproductive system.Making women with diabetes experience menopause earlier [97,98].Early hormone therapy in menopausal women improves BMI and lipid levels in women.

Conclusion
Using bibliometrics, we conducted an analysis to identify the inadequacies, traditional focal points, and potential prospects in the study of MPS across current scientific areas.Treatment and complications are at the core of MPS research, whereas prediction and biomarkers have less literature of high quality.There is a necessity for innovative analytical metrics to measure the real effect of these papers with a high level of citation on clinical application.

Fig. 1 Fig. 2
Fig. 1 The network of authors engaged in 100 top-cited MPS research